The high incidence of breast cancer coupled with earlier diagnosis and more effective therapies has resulted in over 2.5 million American women who are now breast cancer survivors. Excess adiposity is a major adverse prognostic factor post-diagnosis for women with both pre- and postmenopausal breast cancer and may be particularly relevant among women of various minority groups. Despite potential importance, there has never been a clinical trial to determine whether weight loss and maintenance of that loss reduces recurrence risk. Mechanisms that tie adiposity and physical inactivity to increased risk of breast cancer recurrence are not fully understood but include higher endogenous estrogens and insulin, and alterations in cytokines and other factors. Up to 30% of breast cancer survivors experience dysphoria that endures beyond completion of treatment and may be of clinical significance. Psychosocial problems and comorbid medical conditions are likely to be favorably affected by weight loss and increased physical activity in obese breast cancer survivors. We propose a 4-year trial of 800 overweight or obese (BMI >27 and <40 kg/m2) women aged 21 and older who have been diagnosed with stage IC, II, or IIIA breast cancer. The primary specific aim of the project is: (1) To conduct a 4-year vanguard randomized controlled trial with the primary endpoint of weight loss among 800 breast cancer survivors, following all subjects for 2 years after randomization. Our primary hypothesis is that weight loss of at least 7% can be achieved and maintained in this target population. Secondary aims are: (2) To use the Reach, Efficacy/Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to conduct a cost-effectiveness analysis that includes an assessment of the impact of the intervention on medical comorbid conditions; (3) To assess the impact of the intervention on quality of life (QOL), particularly physical functioning and fatigue; and (4) To prospectively collect blood and DNA samples to enable analysis of potential mechanisms and differential response across subgroups. Our research strategy joins experienced investigators from five of the leading cancer centers, a multi-disciplinary team with outstanding experience in diet and exercise interventions, cancer survivorship, nutritional epidemiology, breast oncology trials, and breast cancer outcomes research. The weight loss intervention utilizes a cognitive-behavioral group-based program, telephone counseling and home-based support, developed and tested in previous successful studies conducted by the project investigators. As a vanguard trial, this project will test an intervention using accessible strategies that can be adopted widely in clinical practice and community-based programs and is strategically designed to lead to a fully-powered trial of 2500 subjects for cancer outcomes. If the improvements in QOL that we expect to find can be demonstrated in this trial of 800 survivors, this finding could itself change the norms of clinical practice. If the eventual full trial can document lower recurrence risk with this same intervention, this trial initiates the effort to establish weight control support for breast cancer survivors as a new standard of care.